2({60 -methyl-{60 -hydroxy)-ethyl-4-morpholine-6-trichloromethyl-5-triazine

ABSTRACT

2( Alpha -methyl- Alpha -hydroxy)-ethyl-4-morpholino-6trichloromethyl-s-triazine. The compound has analgesic and antiinflammatory action.

United States Patent Heimberger 2(a-METHYL- cu-HYDROXY)-ETHYL-4- MORPHOLINE-6- TRICHLOROMETHYL-S-TRIAZINE Inventor: Werner Heimberger,

Main, Germany Geutsche GoId-Und Silber-Schudeamstalt vormals Roessler, Frankfurt on Main, Germany Filed: June 1, 1970 Appl. No.: 42,488

Related US. Application Data Hanau on Assignee:

[451 Aug. 15, 1972 594,647, Oct. 31, 1966, Pat. No. 3,522,255.

Foreign Application Priority Data Oct. 30, 1965 Germany ..D 48552 U.S. Cl. ..260/247.5 R, 424/248 Int. Cl. ..C07d 87/40 Field of Search ..260/247.5

Primary Examiner-Alex Mazel Assistant Examiner-Jose Tovar Attorney-Michael S. Striker ABSTRACT 2(a-methyl-a-hydroxy)-ethyl-4-morpholino-6- trichloromethyl-s-triazine. The compound has anal gesic and anti-inflammatory action.

1 Claim, No Drawings 2(1): -IVIETI-IYL-a-HYDROXY)-E'IHYL4- MORPHOLINE-6-TRICIEOROMETHYL5 TRIAZINE CROSS-REFERENCES TO RELATED APPLICATIONS in turn was a division of the above-listed application Ser. No. 594,647, all of which applications were filed by the same inventor in respect of Substituted Triazines."

DESCRIPTION OF THE INVENTION The new compound can for instance be prepared by saponifying morpholino-substituted triazines of the formula R and R are methyl, R is trichloromethyl and R is alkyl or oxy-alkyl of one to six carbon atoms or aryl or hydroxyl aryl, in the presence of a water-miscible organic solvent, especially a lower alkanol, and preferably methanol, and in the presence of about molar quantities of barium hydroxide or sodium hydroxide or potassium hydroxide at a temperature between 0C and the boiling point of the solvent, preferably between about 50 and 70C to form the compound of the invention.

The compounds used as starting materials, for example, can be prepared by the process described in German Pat. No. 1,189,999, which corresponds to US. Pat. No. 3,264,293 of Aug. 2, 1966.

The compound of the invention for example, provides a strong anti-inflammatory action or antiphlogistic action on carrageen edema of the rat's paw upon oral administration in dosages of 10-100 mg/kg.

I The following table indicates the arrest in carrageen edema of the rats paw upon oral administration of mg/kg of an illustrative compound according to the invention (results in percent of edema arrest as compared to control group) and the acute toxicity of such compounds. The antiphlogistic action investigations were carried out according to the method of Domenjoz and C011. Arch. Exp. Pharm. Path. 230, 325 (1957), and the acute toxicity tests were carried out according to the method of Miller & Tainter, Proc. Soc. Exper. Biol. and Med. 57, 261 (1944) with a 24 hour observation period.

TABLE Arrest in carrageen Y edema at 30 mg/kg LD 50 mg/kg dosage oral rat rat, oral D 9220 57 ca. 2000 D 9220 2(a-methyl-a-hydroxy)-ethyl-4morpholino- 6-trichloro-methyl-s-triazine.

The compound has good anti-inflammatory activity and the indications as anti-inflammatory agents are as follows:

chronic arthritis illnesses of a traumatic nature post-traumatic infiammations swellings on fractures thrombophlebitis in every form (including postoperative) bursitis synovitis collagenoses (polymyositis, periarthritis) gout intraperitoneal adhesions The compound of the invention can be used, if desired, also in combination with other medicaments in the form of pharmaceutical compositions suited for enteral and parenteral application.

The enteral administration can, for instance, be effected in the form of tablets, capsules, pills, dragees, suppositories, oily and aqueous solutions or suspensions and emulsions. The parenteral administration can be effected in the form of injectable oily and aqueous solutions or suspensions and emulsions.

The dosage, depending upon the form of administration, can be between 0.1 and 500 mg, one or more times a day.

The following examples will serve to illustrate the invention.

EXAMPLE 1 50 g of 2(a-ethoxycarbonyloxy--a-methyl)-ethyl-4- morpholino--trichloromethyl-s--triazine were dissolved in 300 ml of methanol and the solution heated to boiling. 42 g of Ba(OI-I) -8H O were dissolved in 400 ml of hot methanol and such solution added to the triazine solution over a 3 hour period while the latter was constantly boiled. The triazine solution which initially was clear became cloudy as the saponification proceeded upon addition of the Ba( OH solution. The reaction mixture was then boiled down without first separating the solids and the residue stirred up with dilute HCl whereupon CO was set free. The water-insoluble portion was taken up in methylene chloride. After such solution had been washed neutral it was boiled down. The residue was triturated with water whereupon it crystallized. The yield of 2(a-methyl-ahydroxy)-ethyl-4-morpholino-6-trichloromethyl-striazine was 18 g or 43.5 percent of theory. lts melting point was 72 82C.

EXAMPLE 2 solution was then adjusted to a pH of 5 with concentrated HCl whereby CO was liberated and the solution concentrated under vacuum. The residue was stirred up with water whereby 51 g of 2(a-methyl-a-hydroxy)- ethyl-4-morpholino-6trichloromethyl-s-triazine were obtained.

3,684,806 3 4 The following table gives the formulas of the starting What is claimed as new and desired to be protected malefials Products of the examples- For Simplicity by Letters Patent is set forth in the appended claim: the trlazme "8 l. The compound which is 2(a -mcthyl-a-hydroxy)- ethyl-4-morpholino-6-trichloromethyl-s-triazinc.

t a: t

will be represented therein by the symbol Example Starting material End product 1m l O I! C(CHmOCOCEILi C(ClIa)2()l{ (JluC- Cl C- L N II v N H x) C(CHa)2OCOCH3 /C(Cl'la)z0ll ohc I ClaC- L N ]I b N H d) 

